title: The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol.
abstract: We have determined the gene expression profile induced by 17 alpha-ethynyl estradiol (EE) in Ishikawa cells, a human uterine-derived estrogen-sensitive cell line, at various doses (1 pM, 100 pM, 10 nM, and 1 microM) and time points (8, 24, and 48 h). The transcript profiles were compared between treatment groups and controls (vehicle-treated) using high-density oligonucleotide arrays to determine the expression level of approximately 38,500 human genes. By trend analysis, we determined that the expression of 2560 genes was modified by exposure to EE in a dose- and time-dependent manner (p </= 0.0001). The annotation available for the genes affected indicates that EE exposure results in changes in multiple molecular pathways affecting various biological processes, particularly associated with development, morphogenesis, organogenesis, cell proliferation, cell organization, and biogenesis. All of these processes are also affected by estrogen exposure in the uterus of the rat. Comparison of the response to EE in both the rat uterus and the Ishikawa cells showed that 71 genes are regulated in a similar manner in vivo as well as in vitro. Further, some of the genes that show a robust response to estrogen exposure in Ishikawa cells are well known to be estrogen responsive, in various in vivo studies, such as PGR, MMP7, IGFBP3, IGFBP5, SOX4, MYC, EGR1, FOS, CKB, and CCND2, among others. These results indicate that transcript profiling can serve as a viable tool to select reliable in vitro systems to evaluate potential estrogenic activities of target chemicals and to identify genes that are relevant for the estrogen response.
authors.affiliation: Miami Valley Innovation Center, The Procter and Gamble Company, Cincinnati, Ohio 45253, USA.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: Naciff
authors.forename: Zubin S
authors.initials: ZS
authors.lastname: Khambatta
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Thomason
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Carr
authors.forename: Jay P
authors.initials: JP
authors.lastname: Tiesman
authors.forename: David W
authors.initials: DW
authors.lastname: Singleton
authors.forename: Sohaib A
authors.initials: SA
authors.lastname: Khan
authors.forename: George P
authors.initials: GP
authors.lastname: Daston
mesh_terms: D000818:Animals; D002460:Cell Line; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D020869:Gene Expression Profiling; D005796:Genes / Q000235:genetics / Q000502:physiology; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism; D014599:Uterus / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004997:Ethinyl Estradiol